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Benzazepine derivatives useful as vasopressin antagonists

Inactive Publication Date: 2011-03-24
OTSUKA PHARM CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0143]According to the present invention, a novel benzazepine compound that has excellent properties, such as the maintenance of the blood level of tolvaptan for a long period of time enabling to provide the desired pharmaceutical effects, can be provided.
[0144]When administered into the human body, Compound (1) of the invention or a salt thereof can be easily converted into tolvaptan, which is an active ingredient.
[0145]Further, Compound (1) of the invention or a salt thereof is readily crystallized and easy to handle. Furthermore, Compound (1) of the invention or a salt thereof has excellent chemical stability.
[0146]A composition that can provide pharmaceutical effects equivalent to that of a useful drug tolvaptan can be provided in various forms by using Compound (1) of the invention or a salt thereof.

Problems solved by technology

However, because of its low water solubility, tolvaptan has problems in that it is poorly absorbed from the gastrointestinal tract, and its dosage form and administration route are limited.

Method used

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  • Benzazepine derivatives useful as vasopressin antagonists
  • Benzazepine derivatives useful as vasopressin antagonists
  • Benzazepine derivatives useful as vasopressin antagonists

Examples

Experimental program
Comparison scheme
Effect test

example 1

{7-Chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinate

[0148]Tolvaptan (1.0 g, 2.2 mmol), succinic anhydride (0.33 g, 3.3 mmol), and 4-dimethylaminopyridine (DMAP) (27 mg, 0.22 mmol) were added to 1-methyl-2-pyrolidone (3 ml), and the mixture was stirred at 100° C. for 1 hour. Water was added to the reaction mixture, and the resulted precipitates were collected by filtration. The precipitates were purified using silica gel flash chromatography (n-hexane:ethyl acetate=50:50→20:80). The purified product was concentrated under reduced pressure. The residue was dissolved in aqueous acetonitrile, and then freeze-dried to obtain 300 mg of {7-chloro-1-[2-methyl-4-(2-methyl-benzoylamino)-benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinate as white amorphous solid.

[0149]1H-NMR (DMSO-d6, 100° C.) δ ppm:

[0150]1.6-2.1 (4H, m), 2.37 (6H, s), 2.5-2.6 (2H, m), 2.6-2.7 (2H, m), 3.0-4.3 (2H, m), 5.9-6.0 (1H, m), 6.8-7.1 (2H, m), 7.1-7.3 (...

example 2

Sodium {7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinate

[0151]A sodium hydrogen carbonate (46 mg, 0.55 mmol) aqueous solution (2 ml) was added to a methanol solution (2 ml) of {7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinate (0.30 g, 0.55 mmol), and the mixture was stirred at room temperature for 1 hour. Methanol was distilled off under reduced pressure at about 30° C. The resulting solution was freeze-dried to obtain 0.29 g (94%) of sodium {7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinate as amorphous.

[0152]1H-NMR (DMSO-d6, 100° C.) δ ppm:

[0153]1.70-2.10 (4H, m), 2.19 (2H, t, J=7.1 Hz), 2.37 (6H, s), 2.56 (2H, t, J=7.1 Hz), 3.05-3.50 (1H, m), 3.65-4.25 (1H, m), 5.85-5.95 (1H, m), 6.75-6.90 (1H, m), 6.90-7.10 (2H, m), 7.15-7.55 (6H, m), 7.58 (1H, s), 9.80 (1H, br).

example 3

Potassium {7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinate

[0154]Amorphous of potassium {7-chloro-1-[2-methyl-4-(2-methylbenzoylamino)benzoyl]-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl}succinate was obtained in a similar manner as in the above Example 2.

[0155]1H-NMR (DMSO-d6, 100° C.) δ ppm:

[0156]1.70-2.10 (4H, m), 2.16 (2H, t, J=7.1 Hz), 2.37 (6H, s), 2.48 (2H, t, J=7.1 Hz), 2.95-3.50 (1H, m), 3.70-4.25 (1H, m), 5.85-5.95 (1H, m), 6.75-6.90 (1H, m), 7.00-7.15 (2H, m), 7.20-7.45 (6H, m), 7.58 (1H, s), 9.77 (1H, br).

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Abstract

The present invention provides a benzazepine compound that can maintain for a long period of time the blood level of tolvaptan enabling to provide the desired pharmaceutical effects. The benzazepine compound of the present invention is represented by general formula (1)wherein R1 represents a —CO—(CH2)n—COR2 group (wherein n is an integer of 1 to 4, and R2 is (2-1) a hydroxy group; (2-2) a lower alkoxy group optionally substituted with a hydroxy group, a lower alkanoyl group, a lower alkanoyloxy group, a lower alkoxycarbonyloxy group, a cycloalkyloxycarbonyloxy group, or 5-methyl-2-oxo-1,3-dioxo-4-yl; or (2-3) an amino group optionally substituted with a hydroxy-lower alkyl group), or the like.

Description

TECHNICAL FIELD[0001]The present invention relates to a novel benzazepine compound and a pharmaceutical preparation.BACKGROUND ART[0002]Tolvaptan represented by the following formula (2) is a known compound, and is disclosed, for example, in U.S. Pat. No. 5,258,510 (Example 1199).[0003]Tolvaptan is known to be useful as a vasopressin antagonist having aquaretic efficacy (Circulation, 107, pp. 2690-2696 (2003)). However, because of its low water solubility, tolvaptan has problems in that it is poorly absorbed from the gastrointestinal tract, and its dosage form and administration route are limited. From the viewpoint of medical treatment, the development of a new drug that can maintain for a long period of time the blood level of tolvaptan enabling to provide the desired pharmaceutical effects has been desired.DISCLOSURE OF THE INVENTION[0004]An object of the present invention is to provide a novel benzazepine compound that has excellent properties, such as the maintenance of the blo...

Claims

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Application Information

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IPC IPC(8): A61K31/55C07D223/16C07D403/12C07F9/553C07D405/12C07D413/12C07D401/12C07D405/14C07K5/083A61K31/675A61K38/06A61K38/05A61P9/12A61P9/00A61P7/02
CPCC07D223/16C07F9/5535C07D405/12Y02P20/55A61P13/02A61P43/00A61P7/00A61P7/02A61P7/10A61P7/12A61P9/00A61P9/02A61P9/08A61P9/10A61P9/12A61P9/14
Inventor KONDO, KAZUMIMENJO, YASUHIROTOMOYASU, TAKAHIROMIYAMURA, SHINTOMOHIRA, YUSOMATSUDA, TAKAKUNIYAMADA, KEIGOKATO, YUSUKE
Owner OTSUKA PHARM CO LTD
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